T lymphocyte-derived IFN-γ facilitates breast cancer cells to pass the blood-brain barrier: An in vitro study corroborating translational data
Rute M.S.M. Pedrosa,
Johan M. Kros,
Benjamin Schrijver,
Cor Berrevoets,
Rute B. Marques,
Casper C.H.J. van Eijck,
Reno Debets,
PieterJ.M. Leenen,
Willem A. Dik,
DanaA.M. Mustafa
Affiliations
Rute M.S.M. Pedrosa
Department of Pathology, The Tumor Immuno-Pathology Laboratory, Erasmus University Medical Center, Rotterdam, the Netherlands
Johan M. Kros
Department of Pathology, The Tumor Immuno-Pathology Laboratory, Erasmus University Medical Center, Rotterdam, the Netherlands; Corresponding author. Laboratory for Tumor-ImmunoPathology / Dept. of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands, Dr. Molewaterplein 40, 3015GD, Rotterdam, the Netherlands.
Benjamin Schrijver
Department of Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands
Cor Berrevoets
Department of Medical Oncology, Laboratory of Tumor Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands
Rute B. Marques
Department of Urology, Erasmus University Medical Center, Rotterdam, the Netherlands
Casper C.H.J. van Eijck
Department of Surgery, Erasmus University Medical Center, Rotterdam, the Netherlands
Reno Debets
Department of Medical Oncology, Laboratory of Tumor Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands
PieterJ.M. Leenen
Department of Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands
Willem A. Dik
Department of Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands
DanaA.M. Mustafa
Department of Pathology, The Tumor Immuno-Pathology Laboratory, Erasmus University Medical Center, Rotterdam, the Netherlands
The appearance of brain metastasis is the most serious complication of breast cancer with mostly fatal outcomes. To reach the brain, tumor cells need to pass the blood-brain barrier (BBB). The molecular mechanisms underlying penetration of the BBB are largely unknown. Previously we found that tumor-infiltrating T lymphocytes enhance the development of brain metastasis of estrogen receptor-negative (ER-) breast cancer. In the current study, we investigate the contribution of T lymphocytes and the IFN-γ pathway in enabling breast cancer cells to pass the in vitro BBB. CD8+ cells display the strongest stimulatory effect on breast cancer cell passage. We show that inhibition of the IFN-γ receptor in MDA-MB-231 breast cancer cells, or neutralization of soluble IFN-γ, impairs the in vitro trespassing of breast cancer cells. Importantly, we validated our findings using gene expression data of breast cancer patients. The CXCL-9,-10,-11/CXCR3 axis, dependent on IFN-γ signaling activity, was overexpressed in primary breast cancer samples of patients who developed brain metastasis. The data support a role for T-lymphocytes and the IFN-γ pathway in the formation of brain metastasis of ER-breast cancer, and offer targets to design future therapies for preventing breast cancer cells to cross the BBB.
